Abstract Over 25 million people have died of AIDS, making it one of the largest public health crises in history. There are over 33 million people with HIV world-wide. The majority of new HIV cases occur before age 25, and within marginalized populations. Syndemics theory postulates that multiple emerging and converging psychosocial epidemics are the driving mechanisms that cause HIV transmission. We are proposing that a developmental interpretation and application of syndemics theory is needed in order to explain HIV risk. Sexual minority youth (youth who endorse some level of same-sex attraction, behavior, and/or identity) are an ideal population to use as a model for testing the longitudinal development of syndemic processes. Sexual minority youth are highly marginalized, poorly understood, and severely underserved. They experience multiple psychosocial problems of epidemic proportions that are considered the core components of the syndemic effect. Compared with heterosexual youth, sexual minority youth are up to 5 times more likely to use drugs, 7 times more likely to be victimized, 6 times more likely to have mental health problems, and 5 times more likely to engage in HIV risk behavior. Yet longitudinal studies with sexual minority youth have rarely been conducted due to a host of cultural and methodological barriers. The overarching goal of this research project is to examine substance use and HIV risk behaviors in a longitudinal study of sexual minority youth and a matched comparison group of heterosexual youth. Due to the many important features of the proposed methodology and theory, this will be the first youth study of its kind. These features include the: (A) longitudinal, quasi-experimental design, (B) evaluation of individual growth or change in adolescent substance use and risky sexual behaviors over time, (C) examination of mediators and moderators of risk for substance use and risky sexual behavior, and (D) identification of risk and protective factors associated with the convergence of these multiple emerging epidemics and how they lead to HIV/AIDS. Results from this project will generate a wealth of information about the development of health problems among this highly vulnerable and marginalized group. They will provide empirical support for a developmental interpretation and application of the syndemics framework. And they will serve as a model for understanding how syndemic processes unfold in marginalized populations to raise risk for HIV/AIDS.